Parkinson's disease (PD) is a progressive disorder, which can begin with mild limb stiffness and infrequent tremors, which progress over a period of ten or more years to frequent tremors and memory impairment, and ultimately to uncontrollable tremors and dementia. Parkinson's disease affects about 10 million people world-wide. The disease produces a slowly-increasing disability in purposeful movement. A perceived pathophysiological cause of Parkinson's disease is progressive destruction of dopamine-producing cells in the basal ganglia, which comprise the pars compacta of the substantia nigra, a basal nuclei located in the brain stem. Loss of dopamineric neurons results in a relative excess of acetylcholine.
The understanding that parkinsonism is a syndrome of dopamine deficiency and the discovery of levodopa as an important drug for the treatment of the disease were the logical culmination of a series of related basic and clinical observations, which serves as the rationale for drug treatment. Appropriate management of a patient with PD is possible in the first 5-7 years of treatment, after which time a series of often debilitating complications, together referred to as late motor fluctuations (LMF) occur. Thus, effective treatment of Parkinson's disease can be very difficult considering the complexity of the disease etiology and progression.
Current treatments for PD include drugs, ablative surgical intervention, and/or neural stimulation. Drug treatments or therapies may include levodopa; carbidopa; benserazide; entacapone; dopamine agonists like rotigotine, pramipexole, ropinirole, apomorphine; monoamine oxidase-B (MAO-B) inhibitors like selegiline, rasagiline, safinamide, tranylcypromine; COMT inhibitors like entacapone, tolcapone; and glutamate antagonists like amantadine. Unfortunately, such drug therapies frequently become less effective or ineffective over the time. A PD patient may require multiple drugs in combination to extend the time period of efficacy of drug therapies.
It is believed that treatment with levodopa, the most effective antiparkinson drug, may facilitate or even promote the appearance of LMF. Dopamine agonists are employed as a treatment alternative, but they do not offer the same degree of symptomatic relief to patients as levodopa does. Drug treatments additionally have a significant likelihood of inducing undesirable physical side effects. For example, motor function complications, such as uncontrollable involuntary movements (dyskinesias), are a particularly common side effect.
Systemically-administered anticholinergic drugs (such as benzhexol and orphenedrine) have also been used to treat Parkinson's disease and act by reducing the amount of acetylcholine produced in the brain, and thereby redress the dopamine/acetylcholine imbalance present in Parkinson's disease. Unfortunately, about 70% of patients taking systemically-administered anticholinergics develop serious neuropsychiatric side effects, including hallucinations, dyskinetic movements, and other effects resulting from wide anticholinergic distribution, including vision effects, difficulty swallowing, dry mouth and urine retention. Furthermore, drug treatments may induce undesirable cognitive side effects, such as confusion and/or hallucinations.
Among available treatment options, MAO-B inhibitors prolong the activity of both endogenously- and exogenously-derived dopamine, making them an option either as a monotherapy in early Parkinson's disease or as an adjunctive therapy in patients treated with levodopa who are experiencing motor complications. Selective, irreversible MAO-B inhibitors are recommended due to their safety, tolerability, and easier clinical handling. In addition to symptomatic benefits, experimental data suggest that MAO-B inhibitors may be neuroprotective through MAO-B inhibition and other mechanisms that have yet to be clearly defined. The two available MAO-B inhibitors approved for use in the United States are N-propargylamine derivatives: selegiline (methyl-(1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine) and rasagiline (N-propargyl-1-(R)aminoindan). Both selegiline and rasagiline are available in various forms for the treatment of Parkinson's disease. Selegiline is available as conventional tablets, capsules—ELDEPRYL®, extended release films—EMSAM®, orally disintegrating tablets—ZELAPAR®. Rasagiline is available as conventional tablets—AZILECT®, available in 0.5 mg and 1 mg strengths.
Improved treatments for Parkinson's disease are needed, which provide better patient compliance with more convenient dosing and easy-to-administer dosage forms. Furthermore, clinical studies have shown that up to 82% of patients with Parkinson's disease have swallowing difficulties and many such patients tend to dribble. Accordingly, dosage forms like fast-dispersing formulations are particularly preferred since they will disintegrate rapidly in the mouth, thereby minimizing the dosage-administration difficulties, making it easier for patients to take, and making it easier for care-givers to administer. Treatments for Parkinson's disease that make use of different dosage forms have been reported. For example, US 2015/031774, US 2008/107729, US 2004/091525, WO 2009/02084, and US 2012/122993 relate to orally-disintegrating or fast-acting dosage forms.
For Parkinson's disease treatment, maximum benefits are provided during the first few months of medication administration. However, patients taking antiparkinson drugs for a longer period are prone to the “wearing-off” effect, a tendency for the effectiveness of the drug to be lost with time. Hence, the dose of the medication will often have to be increased with time. Moreover, as the dose of the medication is increased, some patients begin to experience side effects, which include anxiety, agitation, dyskinesia, vomiting, low blood pressure, hallucination and nausea, further limiting the treatment options. Sometimes an “on-off effect,” where the symptoms become sporadic and unpredictable over a period of time, is also experienced. Additionally, the Parkinson's disease condition itself causes discomfort in holding and/or swallowing dosage form due to involuntary movements, which can severely compromise patient compliance. Considering such factors, a formulation, comprising MAO-B inhibitors like N-propargylamine derivatives, that increases bioavailability and can be administered at lower doses than conventional dosage forms, with similar clinical benefits, is desirable. Such a formulation would increase compliance in those patients who report adverse events after initial treatment with conventional formulations, or who suffer from dysphagia or related swallowing difficulties.
There remains a clear unmet clinical need in the art for dosage forms comprising N-propargylamine derivatives, such as rasagiline, which offer convenient dosing for the patient and allow for reliable and rapid absorption of the drug.
Accordingly, the present application relates to a method of administering N-propargylamine derivatives for the treatment of Parkinson's disease, and a composition for use in the treatment of Parkinson's disease, which provide a convenient oral dosage form that dissolves/disintegrates in the oral cavity of the patient, and which are particularly useful to patients requiring oral medication but have difficulty in swallowing.